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Study Title and Description

Enhanced stimulant and metabolic effects of combined ephedrine and caffeine.



Key Questions Addressed
1 For [population], is caffeine intake above [exposure dose], compared to intakes [exposure dose] or less, associated with adverse effects on cardiovascular outcomes?
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Primary Publication Information
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TitleData
Title Enhanced stimulant and metabolic effects of combined ephedrine and caffeine.
Author CA Haller,P Jacob,NL Benowitz,
Country
Year 2004
Numbers

Secondary Publication Information
There are currently no secondary publications defined for this study.


Extraction Form: Cardiovascular Design
Design Details
Question... Follow Up Answer Follow-up Answer
What outcome is being evaluated in this paper? Cardiovascular
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What is the objective of the study (as reported by the authors)? The objective of this study was to compare the pharmacokinetics and pharmacodynamics of ephedrine and caffeine taken in combination with those of each drug taken alone.
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Provide a general description of the methods as reported by the authors. Information should be extracted based on relevance to the SR (i.e., caffeine related methods) Subjects Sixteen healthy nonsmokers aged between 18 and 45 years were recruited. The study was open to all races and ethnicities. The subjects were determined to be in good health on the basis of medical history, physical examination, and clinical laboratory tests. Exclusion criteria included the following: pregnancy or lactation, heart disease, hypertension, thyroid disorder, seizures, strokes, diabetes, liver or renal dysfunction, glaucoma, prostate hypertrophy, psychiatric illness, obesity (body mass index > 30), alcohol or substance abuse, cigarette smoking, moderate caffeine use (defined as > 3 caffeinated beverages per day), and prescription medication use. We planned to enroll 4 women taking oral contraceptives to investigate the effects of this commonly used medication on the pharmacologic characteristics of caffeine and ephedrine. Study Design and Procedures This study was a randomized, double-blind, 4-arm crossover design with each subject receiving 4 treatments consisting of ephedrine, caffeine, ephedrine plus caffeine, and placebo. Doses of 200 mg caffeine citrate and lactose placebo were administered in identical gelatin capsules [NOTE: Caffeine citrate, not caffeine]. The treatment sequence was randomized by use of a 4 x 4 Latin square. There was a minimum 1-week washout period between treatments. Scheduling of female subjects did not take into account menstrual cycle phase, although visits were avoided during the first several days of menstruation. On each study day, subjects arrived at 7 AM after an overnight fast and 24-hour abstinence from beverages, drugs, or supplements that contained caffeine, ephedrine, or related sympathomimetics. Urine toxicology screening was performed to assess exposure to illicit drugs. A catheter was inserted into a forearm vein for blood sampling, and vital signs were monitored with a Critikon Dinamap automated blood pressure instrument (GE Medical Systems Information Technologies , Waukesha, Wis). Three predose measurements of heart rate and blood pressure were taken. At 8 AM, subjects received a single oral dose of a study medication with water. They continued fasting for 3 hours after dosing and then were allowed caffeine-free meals and beverages. Blood samples (10 mL) were collected just before dosing and at 30 minutes, 90 minutes, and 2, 3, 4, 6, 8, 12, 18, and 24 hours after dosing. Urine was collected from 0 to 4 hours and 4 to 24 hours after dosing. The collection from 0 to 4 hours was analyzed for epinephrine and norepinephrine levels. Quantitative measurements of caffeine were performed on all blood samples and the total (24-hour) urine collection. Blood samples were centrifuged and separated, and the plasma was frozen at -20° C until analysis. The pH and volume of each urine void were recorded, and an aliquot of the total urine collection was frozen until analysis. Concentrations of caffeine were determined by a liquid chromatography– tandem mass spectrometry method. Statistical Analysis Pharmacokinetic parameters and outcome variables were tested for normality and homogeneity of variances by use of the Bartlett test. Data that failed these tests were log-transformed and tested again for normality. Results were back-transformed to yield geometric means. Parametric data were analyzed by paired Student t tests of mean differences in values between treatment and placebo at all sample times. The Wilcoxon signed rank test was used for pairwise comparison of nonparametric results. Unpaired t tests and the Mann-Whitney U test for nonparametric data were used to analyze sex differences in treatment effects. Statistical significance was defined a priori as a 2-sided alpha < 0.05. All statistical analyses were conducted by use of CoStat software, version 6.201 (CoHort Software, Monterey, Calif).
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How many outcome-specific endpoints are evaluated? 3
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What is the (or one of the) endpoint(s) evaluated? (Each endpoint listed separately) Blood pressure (SBP and DBP)
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List additional health endpoints (separately). 2 Heart rate
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List additional health endpoints (separately).3 Urinary catecholamines (epinephrine and norepinephrine
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List additional health endpoints (separately).4
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List additional health endpoints (separately).5
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List additional health endpoints (separately).6
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Clinical, physiological, other Physiological
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What is the study design? Controlled Trial
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Randomized or Non-Randomized? RCT
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What were the diagnostics or methods used to measure the outcome? Objective
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Optional: Name of Method or short description Vital signs were monitored with a Critikon Dinamap automated blood pressure instrument (GE Medical Systems Information Technologies , Waukesha, Wis. [NOTE: No method provided for urinalysis]
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Caffeine (general) Caffeine (general)
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Coffee, Chocolate, energy drink, gum, medicine/supplement, soda, tea, other?
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Measured or self reported? Measured
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Children, adolescents, adults, or pregnant included? Adults
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What was the reference, comparison, or control group(s)? (e.g. high vs low consumption, number of cups, etc.) Subjects served as their own controls (placebo)
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What were the listed confounders or modifying factors as stated by the authors? (e.g. multi-variable components of models.  Copy from methods) None
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What conflicts of interest were reported? Drs Haller and Benowitz have served as paid expert witnesses in litigation involving adverse events associated with dietary supplements that contain ephedra alkaloids. Dr Jacob has no conflict of interest to disclose.
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Refid 15060505
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What were the sources of funding? This work was supported by United States Public Health Service grants K23AT00069-01 (National Center for Complementary and Alternative Medicine) and DAO2277 and DA012393 (National Institute on Drug Abuse), as well as a General Clinical Research Center Award (5-MO1-RR-00083-40).
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Results & Comparisons

No Results found.